Genital tract infection with Neisseria gonorrhoeae (gonorrhea) does not induce a state of specific protective immunity and can be acquired repeatedly. Despite public health measures, the disease persists at an unacceptably high frequency; there is no vaccine against it, and resistance even to the latest generations of antibiotics continues to emerge. Recent findings have revealed that N. gonorrhoeae subverts the immune system for its own benefit by eliciting innate responses that it can survive and by suppressing specific adaptive responses that would eliminate it. However, this induced immunosuppression can be reversed by treatments that effectively redirect the immune response against N. gonorrhoeae. In a Phase I SBIR project, proof-of-principle has been established for a novel strategy of therapy and prophylaxis against genital gonococcal infection using a mouse model that is accepted as the only currently available animal model. A proprietary product developed by TherapyX, Inc., consisting of interleukin-12 (IL-12) encapsulated in biodegradable microparticles for sustained release is administered intravaginally in mice infected with N. gonorrhoeae. This treatment, termed GenX12, induces anti-gonococcal T-cell and antibody responses against the existing gonococcal infection, both accelerating its clearance and generating protection against re- infection with homologous and heterologous strains for at least several months. In this Phase II application, the dose regimen of GenX12 will be optimized, and initial pharmacokinetics studies on its distribution and uptake after intravaginal administration will be performed, in preparation for subsequent toxicological testing in nonhuman primates. The mechanisms of cross-protection against diverse strains of naturally occurring N. gonorrhoeae will be determined to substantiate the scientific basis for the treatment and to identify parameters of protective immunity that will need to be tested ultimately in humans. In preparation for clinical trials, manufacturing scale-up and product evaluation for batch consistency, purity, uniformity, stability, and other characteristics will be performed. The data obtained in these studies will then be used to create a primate toxicology plan. Along with the preclinical data, this toxicology plan will be incorporated into a briefing package that will b submitted to the FDA in a request for a Type C Meeting.